Calcium/Calmodulin Activated Kinases in Smooth Muscle

血管平滑肌细胞的迁移和增殖发生在发育、创伤、 愈合，血管生成，并有助于血管疾病的进展。已知Ca 2+信号 调节细胞增殖和运动，尽管这些知识还没有很好地整合到分子生物学中。 模型，部分原因是缺乏对Ca 2+依赖性效应机制和目标的洞察。正在进行的工作 由该基金资助的研究集中在一个主要的Ca 2+信号效应器的结构和功能上，即 多功能Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）。 VSM细胞迁移和增殖是尚未获得的“合成表型”细胞的特性，或 失去了分化的收缩蛋白标志物和功能。VSM表型调节 分化的收缩和增殖/迁移状态具有相当大的兴趣和临床重要性， 但并不完全理解。一个新出现的概念，与上一个供资期的结果一致， 疾病或损伤诱导的Ca 2+信号机制和动力学变化有助于 促进血管壁重塑的迁移/增殖性VSM表型的发展。整体 本更新的目的是测试通过特异性CaMKII亚型的Ca 2+信号传导调节VSM的概念 基因转录，是VSM表型的决定因素。 这一概念将通过追求三个目标来检验：1。我们将测试CaMKII调节细胞增殖的假设。 合成表型VSM中的共阻遏物HDAC 4和HDAC 5。转录激活因子MEF 2将被 作为影响基因转录的CaMKII/HDAC 4，5-依赖性靶标进行测试。CaMKII亚型特异性 与该调节途径的偶联被测试。2.）的情况。CaMKII同工酶作为调节剂的功能 将评估VSM中转录抑制因子REST/NRSF的表达和活性，并将评估HDAC 4/5的表达和活性。 作为中介进行测试。3.）第三章CaMK Ⅱ依赖性调节HDAC 4/5和REST在调节 将使用球囊损伤的大鼠颈动脉在体内评价VSM表型和血管重塑 做模特 通过阐明CaMKII同种型调节对血管损伤的反应的功能后果， 这些研究的结果有望为深入了解表型 VSM细胞的调节和Ca 2+信号传导机制以及显著的Ca 2+依赖性 多功能蛋白激酶调节VSM细胞功能并导致血管疾病。

Migration and proliferation of vascular smooth muscle (VSM) cells occurs during development, wound healing, angiogenesis, and contributes to the progression of vascular disease. Ca2+ signals are known to regulate cell proliferation and motility, although this knowledge has not been well integrated into molecular models, due in part to lack of insight into Ca2+-dependent effector mechanisms and targets. Ongoing work funded by this grant has focused on the structure and function of one major Ca2+ signal effector, namely multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII). VSM cell migration and proliferation are properties of "synthetic phenotype" cells that have not acquired, or have lost, differentiated contractile protein markers and function. VSM phenotype modulation between differentiated contractile and proliferative/migratory states are of considerable interest and clinical importance, but are incompletely understood. An emerging concept, consistent with results from the past funding period, is that disease- or injury-induced changes in Ca2+ signaling mechanisms and dynamics contributes to development of the migratory/proliferative VSM phenotype promoting vascular wall remodeling. The overall objective of this renewal is to test the concept that Ca2+ signaling via specific CaMKII isoforms, regulates VSM gene transcription and is a determinant of VSM phenotype. This concept will be tested by pursuing three aims: 1.) We will test the hypothesis that CaMKII regulates the co-repressors HDAC4 and HDAC5 in synthetic phenotype VSM. The transcription activator MEF2 will be tested as a CaMKII/HDAC4,5-dependent target affecting gene transcription. CaMKII isoform specificity in coupling to this regulatory pathway be tested. 2.) The function of CaMKII isozymes as regulators of the transcriptional repressor REST/NRSF expression and activity in VSM will be evaluated and HDAC4/5 will be tested as intermediaries. 3.) The function of CaMKII-dependent regulation of HDAC4/5 and REST in regulating VSM phenotype and vascular remodeling will be evaluated in vivo using the balloon-injured rat carotid artery as a model. By elucidating the functional consequences of CaMKII isoform modulation in response to vascular injury, the results of these studies are expected to provide insights into mechanisms underlying phenotypic modulation of VSM cells and mechanism(s) by which Ca2+ signals and a prominent Ca2+-dependent multifunctional protein kinase modulates VSM cell function and contributes to vascular disease.